1. Field of the Invention.
This invention relates to derivatives of estra 1,3,5(10)triene-17-one, 3-amino compounds. More specifically, it relates to compounds useful as steroid sulfatase inhibitors in estrogen dependent illnesses. Methods of employing these compounds for therapeutic and prophylactic treatment are also provided.
2. Background Information.
It is estimated that approximately 30-40% of all breast cancers are estrogen dependent. In post-menopausal advanced breast cancer patients, the estrogen levels are in order of magnitude higher than in plasma. However, H. L. Bradlow in "A Reassessment of the Role of Breast Tumor Aromatization," Cancer Research, Volume 42, pp. 3382-33865 (1982), detected no active uptake of estrogens by breast tumors, and he also pointed out that the circulating level of estrogen in post-menopausal women would not be sufficient to stimulate tumor growth.
Two pathways are proposed to occur in breast cancer cells to explain the high concentration of estrogens in breast tumors: (1) conversion of androstenedione to estrone by aromatase (aromatose pathway) and (2) conversion of estrone sulfate to estrone by estrone sulfatase (sulfatase pathway). This is disclosed by S. J. Santner, et al. in "In Situ Estrogen Production Via The Estrone Sulfatase Pathway in Breast Tumors: Relative Importance Versus the Aromatose Pathway." J. Clin. Endocrinal Metab., Volume 59, pp. 29-33 (1984) and R. J. Santen, et al. in "Enzymatic Control of Estrogen production in Human Breast Cancer: Relative Significance of Aromatose Versus Sulfatase Pathways." Ann NY Acad. Sci., Volume 464, pp. 126-137 (1986).
Recently more attention has been directed toward the sulfatase pathway. Estrone sulfate is the most abundant circulating estrogen in women and estrone sulfatase has been consistently found in human breast cancer cells. It was reported that a high percentage of .sup.3 H! estrone sulfate was converted to estradiol in different hormone-dependent mammary cancer cell lines MCF-7, R-27, T-47D! but little or no conversion was found in the hormone-independent mammary cancer cell lines (MDA-MB-231, MDA-MB-436). This is disclosed in F. Vignon, et al., "Effect of Plasma Estrogen Sulfate in Mammary Cancer Cells," Endocrinology, Volume 106, pp. 1079-1086 (1980) and J. R. Pasqualini, et al., "Importance of Estrogen Sulfates in Breast Cancer," J. Steroid Biochem, Volume 34, pp. 155-163 (1989). In addition, the conversion of .sup.3 H! estrone sulfate to .sup.3 H! estrone and .sup.3 H! estradiol was also demonstrated by incubating the homogenates of mammary carcinoma tissue in vitro in 23 breast cancer patients and described by N. Wilking, et al. in "Oestrogen Receptors and Metabolism of Oestrone Sulphate in Human Mammary Carcinoma", Eur J. Cancer, Volume 16, pp. 1339-1344 (1980).
Santen, et al., supra, evaluated estrogen production from breast tumor by way of the estrone sulfate to estrone (sulfatase) pathway and compared it with the androstenedione to estrone (aromatose) pathway. When comparing the sulfatase with aromatase activity in human tumors at physiological levels of substrates, the amount of estrone produced through sulfatase was 10 times higher than through the aromatase pathway (2.8 pmol estrone/g protein verses 0.27 pmol/g protein) in human breast tumors. This suggested that the sulfatase pathway is significant and perhaps the primary means of local estrogen production in breast tumor tissues.
Preliminary results indicated the importance of estrone sulfate as a potential source of estrogen to support the growth of estrogen-dependent breast cancer. Potent inhibitors of estrone sulfatase may be potential therapeutic agents for the treatment of estrogen-dependent breast cancer. This was disclosed by Reed and co-workers in PCT/GB 92/01386 published as WO93/05063 and PCT/GB91/00270 published as WO91/13083.
Several groups of compounds have been reported to be estrone sulfatase inhibitors. M. J. Reed, et al. disclosed in "Sulphatase Inhibitors: The Rationale For The Development of a New Endocrine Therapy," Reviews on Endocrine-Related Cancer, Volume 45, pp. 51-62 (1993), the sulfatase inhibitory activities of estrone-3-0-methylthiophosphonates, estrone 3-0 alkyl and aryl sulfonates, estrone-3-0-phosphates and thiophosphonates and estrone sulfamates on MCF-7 cells and in human placental microsomes and breast tumor preparations. In "Estrone Sulfamates: Potent Inhibitors of Estrone Sulfatase With Therapeutic Potential," J. Med. Chem., Volume 37, pp. 219-221 (1994), Nicola M. Howarth, et al. disclosed that estrone 3-0-sulfamates represent a new class of sulfatase inhibitor and are considerably more potent in MCF-7 breast cancer cells than estrone 3-0 methylthiophosphonate.
In spite of the prior art disclosure there remains a very real and substantial need for an inhibitor of estrogen sulfatase that is more metabolically stable, more active and more selective than known compounds having antitumor activity or as synergistic agents with antiestrogen compounds and aromatase inhibitors and for methods of using such compounds.